The long term goal of this study is to increase our understanding of the immune mechanisms involved in the pathogenesis of allergic lung disease and asthma. We are going to study the mechanisms by which NKT cells influence the induction of airway hyperreactivity (AHR), a cardinal feature of asthma. We recently reported that NKT cells are indeed present in the lungs of asthmatic subjects, produce high level of IL-4 &IL-13. In this proposal, first we would like to study the role of NKT cells in induction of airwayhyperreactivity, second we would like to investigate how NKT cell activation can influence T cell polarization and tolerance, and third, we would like to study the interactions between NKT and regulatory T cells. In the first part we will study the role of NKT cells and cytokines in particular TH2 cytokines, IL-4 and IL-13. NKT cells through their limited TCR repertoire recognize glycolipids presented by CD Id. Dendritic cells express CD Id and our preliminary data indicated that the interactions between NKT cells and DCs are essential for induction of AHR. We would like to study the role DC in activation/polarization of NKT cells, in particular role of costimulatory molecules such as ICOS, OX-40 and PD-1 in induction of NKT cells. Our preliminary data indicated that while naive and activated NKT cells, both express high levels of ICOS and OX- 40, PD-1 is only expressed on CD4+ NKT cells. In the second part of the projects we will investigate the role of NKT cells in T cell tolerance. As we know, both atopic and non-atopic individuals are constantly exposed to aeroallergens, leading to protection in the former and severe airway pathology in the later group. A better understanding of the mechanisms resulting in T cell tolerance is a valuable approach towards therapy for diseases. Our preliminary data suggest that upon activation, NKT cells can potentially break T cell tolerance, however, the signals that drive NKT cells into activation or regulation, are as yet undefined. We will study the role of costimulatory molecules, antigen presenting cells and cytokines in abrogation of tolerance by activated NKT cells. In the third part, we will investigate the potential interactions between NKT cells and regulatory T cells, including the importance of regulatory T cells in regulation of AHR. The three parts of project will finally be connected by analyzing whether signals given to NKT cells result in the development of polarized NKT cells whose actions will be studied in vivo and in vitro.